The indications for thrombolytic treatment in normotensive patients with pulmonary embolism (PE) are still the subject of debate, and it also remains questionable whether the efficacy and safety of thrombolysis are similar in men and women. To address the latter issue, the present study analyzed a large population of 428 women and 291 men with acute submassive PE derived from a prospective multicenter registry. Initial treatment consisted either of thrombolysis (<24 hours after diagnosis) or heparin alone. Thirty-day overall mortality was almost identical (11%) in heparin-treated men and women. Early thrombolysis was associated with drastically reduced death rates (2.7% vs 11% in the heparin group, p = 0.033) in men, whereas the reduction was nonsignificant (p = 0.181) in women. Multivariate analysis revealed that early thrombolysis was independently associated with reduced mortality rates in men (odds ratio 0.21, 95% confidence interval 0.05 to 0.96). In comparison, its favorable effect in women was marginal (odds ratio 0.77, 95% confidence interval 0.30 to 1.97). Gender-specific differences were also observed with regard to the reduction of symptomatic PE recurrence (in men, from 21.6% to 8.2%, p = 0.009; in women, from 16.9% to 8.3%, p = 0.049). In contrast, thrombolysis resulted in a more than threefold increase in major bleeding in women (from 8.4% to 27.1%, p <0.001), a more pronounced effect than in men (from 6.9% to 15.1%, p = 0.055). In conclusion, the present study generated the hypothesis that women with submassive PE might benefit less from thrombolytic treatment in terms of survival and PE recurrence and that they could be exposed to a higher bleeding risk compared with men.